Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to heterocychc amide derivatives, pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.
• These heterocychc amides possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity and thus are potentially useful in methods of treatment of a warm-blooded animal such as man.
• the invention also relates to processes for the manufacture of said heterocychc amide derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit glycogen phosphorylase activity in a warm-blooded animal such as man.
• the liver is the major organ regulating glycaemia in the post-absorptive state. Additionally, although having a smaller role in the contribution to post-prandial blood glucose levels, the response of the liver to exogenous sources of plasma glucose is key to an ability to maintain euglycaemia.
• An increased hepatic glucose output (HGO) is considered to play an important role in maintaining the elevated fasting plasma glucose (FPG) levels seen in type 2 diabetics; particularly those with a FPG >140mg/dl (7.8mM).
• Liver glycogen phosphorylase a activity is elevated in diabetic animal models including the db/db mouse and the fa/fa rat (Aiston S et al (2000). Diabetalogia 43, 589-597). Inhibition of hepatic glycogen phosphorylase with chloroindole inhibitors (CP91149 and CP320626) has been shown to reduce both glucagon stimulated glycogenolysis and glucose output in hepatocytes (Hoover et al (1998) J Med Chem 41, 2934-8; Martin et al (1998) PNAS 95, 1776-81). Additionally, plasma glucose concentration is reduced, in a dose related manner, db/db and ob/ob mice following treatment with these compounds.
• Bay K 3401 Studies in conscious dogs with glucagon challenge in the absence and presence of another glycogen phosphorylase inhibitor, Bay K 3401, also show the potential utility of such agents where there is elevated circulating levels of glucagon, as in both Type 1 and Type 2 diabetes. In the presence of Bay R 3401, hepatic glucose output and arterial plasma glucose following a glucagon challenge were reduced significantly (Shiota et al, (1997), Am J Physiol, 273: E868).
• heterocychc amides of the present invention possess glycogen phosphorylase inhibitory activity and accordingly are expected to be of use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia and obesity, particularly type 2 diabetes.
• A is phenylene or heteroarylene
• m is 0, 1 or 2
• n is 0, 1 or 2
• R 1 is independently selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl, N-C 1 . 4 alkylcarbamoyl, NN ⁇ Cwalkyl ⁇ carbamoyl, sulphamoyl, N-C- ⁇ alkylsulphamoyl,
• the two R 1 groups, together with the carbon atoms of A to which they are attached, may form a 4 to 7 membered ring, optionally containing 1 or 2 heteroatoms independently selected from O, S and ⁇ , and optionally being substituted by one or two methyl groups;
• R 4 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, C ⁇ - 4 alkyl, C 2 - 4 alkenyl,
• R is hydrogen, hydroxy or carboxy
• R 3 is selected from hydrogen, hydroxy, C ⁇ alkoxy, C ⁇ - 4 alkanoyl, carbamoyl, C 3 - cycloalkyl
• R 8 is independently selected from hydroxy, C 1 - 4 alkoxyC 1 . 4 alkoxy, hydroxyC 1 - alkoxy, 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl, C 3 . cycloalkyl, C ⁇ - 4 alkanoyl, ⁇ alkoxy, C ⁇ - 4 alkylS(O) b - (wherein b is 0, 1 or 2), C 3 .
• R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents independently selected from oxo, hydroxy, carboxy, halo, nitro, cyano, carbonyl, C ⁇ - 4 alkoxy and heterocyclyl; or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl; R 13 is selected from hydroxy, halo, trihalomethyl and C ⁇ - 4 alkoxy;
• R is independently selected from hydrogen, C ⁇ - alkyl and hydroxyC 1 - 4 alkyl; or a pharmaceutically acceptable salt or pro-drug thereof.
• a compound of formula (1) wherein: is a single or double bond; A is phenylene or heteroarylene; m is 0, 1 or 2; n is 0, 1 or 2; wherein R 1 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, N-C 1 - 4 alkylcarbamoyl, N,N-(C ⁇ - alkyl) 2 carbamoyl, sulphamoyl, N-C 1 - 4 alkylsulphamoyl, N,N-(C ⁇ - 4 alkyl) 2 sulphamoyl, sulfino, sulfo, C 1 - 4 alkyl, C 2 - 4 alkenyl, C 2 - alkynyl, Ci- alkoxy, C ⁇ - alkanoyl, C ⁇ - alkanoyloxy, N-(Ci- 4 alkyl)amino,
• R is hydrogen, hydroxy or carboxy;
• R 3 is selected from hydrogen, hydroxy, Ci- 4 alkanoyl, carbamoyl, C 1 - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), C 5 - cycloalkyl (optionally substituted with 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyano(C 1 - 4 )alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, C- ⁇ alkyl [substituted by 1 or 2 R 8 groups (provided that when there are 2 R groups they are not substituents on the same carbon)] and groups of the formulae B and B' :
• R 8 is independently selected from hydroxy, C ⁇ - alkoxyC ⁇ - 4 alkoxy, hydroxyC ⁇ - alkoxy, 2,2-dimethyl-l,3-dioxolan-4-yl, heterocyclyl, C 1 . 4 alkanoyl, C 1 . 4 alkoxy, C ⁇ - 4 alkanesulfinyl, C 1 - 4 alkanesulfonyl, - ⁇ (OH)CHO, -COCOOR 9 , (R 9 )(R 10 )NCO-, (R 9 )(R 10 )NSO 2 -, -COCH 2 OR ⁇ , (R 9 )(R 10 )N- and -COOR 9 ;
• R 9 and R 10 are independently selected from hydrogen, hydroxy, C ⁇ - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), C 5 - 7 cycloalkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyanoCC ⁇ alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl g, 1,1-dioxotetrahydrothiopyranyl, 2,2-dimethyl-l,3-dioxolan-4-yl and Ci- 4 alkyl substituted by R 13 ;
• R 13 is selected from hydroxy, Ci- 4 alkoxy, heterocyclyl, C ⁇ - alkanoyl, C 1 - 4 alkanesulfinyl, -N(OH)CHO, (R n )(R 12 )NCO-, (R ⁇ )(R 12 )NSO 2 -, -COCH 2 OR ⁇ , (R ⁇ )(R 12 )N- ;
• R 11 and R 12 are independently selected from hydrogen, C ⁇ alkyl, C ⁇ - 4 alkoxy, hydroxyC 1 . alkyl, Ci- 4 alkylS(O)b (wherein b is 0, 1 or 2) ⁇ ); and
• R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6- membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from oxo, hydroxy, carboxy, halo, nitro, nitroso, cyano, isocyano, amino,
• R 3 , R 9 and R 10 (as defined hereinbefore or hereinafter) allows two hydroxy substituents on the alkyl or cycloalkyl group, or one hydroxy substituent and a second substituent linked by a heteroatom (for example alkoxy), then these two substituents are not substituents on the same carbon atom of the alkyl or cycloalkyl group.
• the invention relates to compounds of formula (1) as hereinabove defined or to a pharmaceutically acceptable salt.
• the invention relates to compounds of formula (1) as hereinabove defined or to a pro-drug thereof.
• Suitable examples of pro-drugs of compounds of formula (1) are in-vivo hydrolysable esters of compounds of formula (1). Therefore in another aspect, the invention relates to compounds of formula (1) as hereinabove defined or to an in-vivo hydrolysable ester thereof.
• optically active or racemic forms by virtue of one or more asymmetric carbon atoms
• the invention includes in its definition any such optically active or racemic form which possesses glycogen phosphorylase inhibition activity.
• the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
• the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
• a compound of the formula (1) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which has glycogen phosphorylase inhibition activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
• the formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein.
• certain compounds of the formula (1) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which have glycogen phosphorylase inhibition activity. It is also to be understood that certain compounds of the formula (1) may exhibit polymorphism, and that the invention encompasses all such forms which possess glycogen phosphorylase inhibition activity.
• the present invention relates to the compounds of formula (1) as hereinbefore defined as well as to the salts thereof.
• Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (1) and their pharmaceutically acceptable salts.
• Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula (1) as hereinbefore defined which are sufficiently basic to form such salts.
• Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid.
• Suitable salts include hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates.
• pharmaceutically acceptable salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
• Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• an alkali metal salt such as a sodium or potassium salt
• an alkaline earth metal salt such as a calcium or magnesium salt
• an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• the compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the invention.
• a prodrug may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodrug.
• pro-drugs include in- vivo hydrolysable esters of a compound of the invention or a pharmaceutically-acceptable salt thereof.
• Various forms of prodrugs are known in the art, for examples see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p.
• An in vivo hydrolysable ester of a compound of formula (1) containing carboxy or hydroxy group is, for example.
• Suitable pharmaceutically acceptable esters for carboxy include -ealkoxymethyl esters for example methoxymethyl, Ci-ealkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 - 8 cycloalkoxycarbonyloxyC ⁇ -6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2 ⁇ onylmethyl; and C ⁇ - 6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
• Suitable pharmaceutically-acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
• inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
• ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
• a selection of in-vivo hydrolysable ester forming groups for hydroxy include -ioalkanoyl, for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, C ⁇ oalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-(C ⁇ - 4 )alkylcarbamoyl and N-(di-(C ⁇ - 4 )alkylaminoethyl)-N- (C ⁇ - 4 )alkylcarbamoyl (to give carbamates); di-(d- )alkylaminoacetyl and carboxyacetyl.
• ring substituents on phenylacetyl and benzoyl include aminomethyl, (C ⁇ pattern 4 )alkylaminomethyl and di-((C 1 - 4 )alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
• Other interesting in-vivo hyrolysable esters include, for example, CO-, wherein R A is for example, benzyloxy-(C 1 - )alkyl, or phenyl).
• Suitable substituents on a phenyl group in such esters include, for example, 4-(C ⁇ - 4 )piperazino-(C 1 - 4 )alkyl, piperazino- (C ⁇ - )alkyl and morpholino-(C ⁇ -C 4 )alkyl.
• alkyl includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only.
• C ⁇ - 4 alkyl includes methyl, ethyl, propyl, isopropyl and t-butyl.
• An analogous convention applies to other generic terms, for example "C 2 . alkenyl” includes vinyl, allyl and 1-propenyl and "C 2 . alkynyl” includes ethynyl, 1-propynyl and 2-propynyl.
• hydroxyC ⁇ - alkyl includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and hydroxybutyl.
• hydroxyethyl includes 1 -hydroxyethyl and 2- hydroxyethyl.
• hydroxypropyl includes 1-hydroxypropyl, 2-hydroxypropyl and 3- hydroxypropyl and an analogous convention applies to terms such as hydroxybutyl.
• dihydroxyC ⁇ - 4 alkyl includes dihydroxyethyl, dihydroxypropyl, dihydroxyisopropyl and dihydroxybutyl.
• dihydroxypropyl includes 1,2-dihydroxypropyl and 1,3- dihydroxypropyl. An analogous convention applies to terms such as dihydroxyisopropyl and dihydroxybutyl.
• halo refers to fluoro, chloro, bromo and iodo.
• dihaloC ⁇ - 4 alkyl includes difluoromethyl and dichloromethyl. The term includes trifluoromethyl.
• Examples of "5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof are: l,3-dioxolan-4-yl, 2-methyl-l,3-dioxolan-4-yl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2- dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl; l,3-dioxan-2-yl.
• Examples of “C ⁇ - 4 alkoxy” include methoxy, ethoxy, propoxy and isopropoxy.
• Examples of “Ci- ⁇ alkoxy” include the examples of “C 1 - 4 alkoxy” and additionally butyloxy, t- butyloxy, pentoxy and l,2-(methyl) 2 propoxy. Examples of include formyl, acetyl and propionyl.
• Examples of “C ⁇ _ 6 alkanoyl” include the example of “C ⁇ - 4 alkanoyl” and additionally butanoyl, pentanoyl, hexanoyl and l,2-(methyl) 2 propionyl.
• Examples of “C ⁇ - 4 alkanoyloxy” are formyloxy, acetoxy and propionoxy.
• Examples of “C ⁇ - 6 alkanoyloxy” include the examples of “C ⁇ - 4 alkanoyloxy” and additionally butanoyloxy, pentanoyloxy, hexanoyloxy and l,2-(methyl) 2 propionyloxy.
• Examples of "N-(C 1 . alkyl)amino” include methylamino and ethylamino.
• Examples of “N,N-(Ci- 4 alkyl) 2 amino” include N-N- (methyl) 2 amino, N-N-(ethyl) 2 amino and N-ethyl-N-methylamino.
• N-(C 1 - 4 alkyl)carbamoyl are methylcarbamoyl and ethylcarbamoyl.
• Examples of "N,N-(C ⁇ - alkyl) 2 carbamoyl” are N,N-(methyl) 2 carbamoyl, N,N-(ethyl) 2 carbamoyl and N- methyl-N-ethylcarbamoyl.
• N-(C 1 - 4 alkyl)sulphamoyl are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.
• Examples of "N,N-(C ⁇ - 4 alkyl) 2 sulphamoyl” are
• C 1 - 4 alkoxyC ⁇ - alkoxy are methoxymethoxy, ethoxymethoxy, ethoxyethoxy and methoxyethoxy.
• hydroxyC 1 - 4 alkoxy are hydroxyethoxy and hydroxypropoxy.
• hydroxypropoxy are 1 -hydroxypropoxy, 2-hydroxypropoxy and 3 -hydroxypropoxy.
• Examples of "cyano(C 1 . )alkyl” are cyanomethyl, cyanoethyl and cyanopropyl.
• Examples of “C 5 - cycloalkyl” are cyclopentyl, cyclohexyl and cycloheptyl.
• Examples of “C 3 - scycloalkyl” and “C 3 - cycloalkyl” include “C 5 - cycloalkyr', cyclopropyl, cyclobutyl and cyclooctyl.
• Examples of "C 3 - 6 cycloalkyl” includelde cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• aminoC 1 - 4 alkyl includes aminomethyl, aminoethyl, aminopropyl, aminoisopropyl and aminobutyl.
• aminoethyl includes 1 -aminoethyl and 2- aminoethyl.
• aminopropyl includes 1 -aminopropyl, 2-aminopropyl and 3- aminopropyl and an analogous convention applies to terms such as aminoethyl and aminobutyl.
• sulfo means HOSO 2 - .
• sulfino means HO 2 S- .
• C ⁇ - alkylS(O) b (wherein b is 0,1 or 2)” include methylthio, ethylthio, propylthio, methanesulphinyl, ethanesulphinyl, propanesulphinyl, mesyl, ethanesulphonyl, propanesulphonyl and isopropanesulphonyl.
• C 3 - 6 cycloalkylS(O) b examples include cyclopropylthio, cyclopropylsulphinyl, cyclopropylsulphonyl, cyclobutylthio, cyclobutylsulphinyl, cyclobutylsulphonyl, cyclopentylthio, cyclopentylsulphinyl and cyclopentylsulphonyl.
• arylS(O) b examples include phenylthio, phenylsulphinyl and phenylsulfonyl.
• benzylS(O) b examples include benzylthio, benzylsulfinyl and benzylsulfonyl.
• heterocyclylS(O) b examples include pyridylthio, pyridylsulfinyl, pyridylsulfonyl, imidazolylthio, imidazolylsulfinyl, imidazolylsulfonyl, pyrimidinylthio, pyrimidinylsufinyl, pyrimidinylsulfonyl, piperidylthio, piperidylsulfinyl and piperidylsulfonyl.
• Heterocyclyl is a saturated, partially saturated or unsaturated, optionally substituted monocyclic ring containing 5 to 7 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxide(s). Examples and suitable values of the term
• heterocyclyl are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, dioxolanyl, thiadiazolyl, piperazinyl, isothiazohdinyl, triazolyl, tetrazolyl, pyrrolidinyl, 2-oxazolidinonyl, 5-isoxazolonyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-5-yl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, pyrimidyl, pyrazinyl,
• a "heterocyclyl” is morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4- oxopydridyl, 2-oxopyrrohdyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl
• heterocyclyl is oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thizoyl, thiadiazolyl, pyridyl, imidazolyl, furyl, thienyl, morpholine, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, and piperazinyl.
• Suitable optional substituents for "heterocyclyl” as a saturated or partially saturated ring are 1, 2 or 3 substituents independently selected from halo, cyano, hydroxy, C ⁇ - alkyl, - 4 alkoxy and C 1 - alkylS(O) b (wherein b is 0, 1 or 2).
• Further suitable substituents for "heterocyclyl” as a saturated or partially saturated ring are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulf ⁇ nyl and methylsulfonyl.
• Suitable optional susbtituents for "heterocyclyl" as an unsaturated ring are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, C ⁇ - alkyl, Ci- 4 alkoxy, C ⁇ - 4 alkylS(O)b (wherein b is 0, 1 or 2), N-(Ci alkyl)amino and N,N-(Ci- 4 alkyl) 2 amino.
• heterocyclyl as an unsaturated ring
• substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.
• Examples of "(heterocyclyl)C 1 - alkyl” are morpholinomethyl, morpholinethyl, morpholinylmethyl, morpholinylethyl, piperidinomethyl, piperidinoethyl, piperidylmethyl, piperidylethyl, imidazolylmethyl, imidazolylethyl, oxazolylmethyl, oxazolylethyl, 1,3,4- oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl, pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl, pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and piperazinylethyl.
• aryl are optionally substituted phenyl and naphthyl.
• aryl(C 1 - )alkyl are benzyl, phenethyl, naphthylmethyl and naphthylethyl.
• Suitable optional substituents for "aryl" groups are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, C ⁇ - alkyl, C ⁇ - alkoxy, C ⁇ - alkylS(O)b (wherein b is 0, 1 or 2), and N,N-(C 1 - 4 alkyl) 2 amino.
• Further suitable optional susbtituents for "aryl” groups are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.
• Heteroarylene is a diradical of a heteroaryl group.
• a heteroaryl group is an aryl, monocyclic ring containing 5 to 7 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen.
• heteroarylene are oxazolylene, oxadiazolylene, pyridylene, pyrimidinylene, imidazolylene, triazolylene, tetrazolylene, pyrazinylene, pyridazinylene, pyrrolylene, thienylene and furylene.
• Suitable optional substituents for heteroaryl groups are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, C 1 - alkyl, C ⁇ - 4 alkoxy, Ci- alkylS(O)b (wherein b is 0, 1 or 2), N-(C ⁇ - 4 alkyl)amino and N,N-(C ⁇ - 4 alkyl) 2 amino.
• heteroaryl groups are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.
• compounds of formula (1) in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (1), in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (1), and in a further alternative embodiment are provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula (1).
• m is 1 or 2.
• m is 1.
• R 4 is selected from hydrogen, halo, cyano, hydroxy, fluoromethyl, difluoromethyl and trifluoromethyl.
• R 4 is hydrogen or halo.
• R 4 is selected from hydrogen, chloro or bromo.
• R 4 is chloro
• A is phenylene. In another aspect of the invention A is heteroarylene.
• A is selected from phenylene, pyridylene, pyrimidinylene, pyrrolylene, imidazolylene, triazolylene, tetrazolylene, oxazolylene, oxadiazolylene, thienylene and furylene.
• n is 0 or 1. In one aspect preferably n is 1.
• n 0.
• n 2
• the two R 1 groups together with the carbon atoms of A to which they are attached, form a 4 to 7 membered ring, optionally containing 1 or 2 heteroatoms independently selected from O, S and N, conveniently such a ring is a 5 or 6 membered ring containing two O atoms (ie a cyclic acetal).
• the two R 1 groups together form such a cyclic acetal, preferably it is not substituted.
• the two R 1 groups together are the group -O-CH 2 -O-.
• R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl and C ⁇ - alkoxy.
• R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O) b C 1 - alkyl (wherein b is 0, 1 or 2), C ⁇ - alkyl and - 4 alkoxy.
• R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O) b Me (wherein b is 0, 1 or 2), methyl and methoxy.
• R 1 is Ci- alkyl
• R 1 is selected from halo and d- 4 alkoxy. In another embodiment preferably R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-.
• R 2 is hydrogen. In another aspect of the invention R 2 is carboxy.
• R is hydroxy.
• R 2 is hydrogen.
• Suitable values for R as heterocyclyl are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-oxopyrrolidyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, and 1,2,
• R 3 tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1 J -dioxotetrahydrothiopyranyl.
• R 3 is selected from hydrogen, hydroxy, C ⁇ . alkoxy, C ⁇ - alkanoyl, carbamoyl, C 3 - cycloalkyl (optionally substituted with 1 or 2 hydroxy groups, cyano(C ⁇ - )alkyl, phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, iso
• R is selected from hydroxy, halo, trifluoromethyl and C ⁇ - alkoxy;
• R 11 is selected from hydrogen, C 1 - 4 alkyl and hydroxyC ⁇ - 4 alkyl.
• R 3 is selected from cyanoC ⁇ - alkyl and C 1 - 4 alkyl (optionally substituted by 1 or 2 of R 8 groups);
• R 8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, C ⁇ alkoxy, C 1 . 4 alkanoyl, Q.
• R 9 and R 10 are independently selected from hydrogen, hydroxy, Ci- 4 alkyl optionally substituted with R 13 (wherein R 13 is Ci- 4 alkoxy or hydroxy); or
• R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring may be optionally substituted on carbon by 1 or 2 hydroxy groups or carboxy groups), or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -
• O- group may be replaced by a methyl
• R 3 is selected from cyanoC 1 - 4 alkyl and C 1 - alkyl
• R 8 is independently selected from hydroxy, 2,2-dimethyl-l,3-dioxolan-4-yl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, C ⁇ - 4 alkoxy, C 1 .
• R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 6-membered ring selected from piperidine, 4-hydroxy piperidine, pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of 3,4-dihydroxypyrrolidine.
• R 3 is selected from hydroxypropyl, 2-butanol, 3-hydroxy-2-hydroxymethyl-propyl, 2,3-dihydroxypropyl, l,3-dihydroxyprop-2-yl, (2,2- dimethyl-l,3-dioxolan-4-yl)methyl, (2,2-dimethyl-l,3-dioxan-4-yl)methyl, (2,2-dimethyl- l,3-dioxan-5-yl)methyl, (2-oxo-l,3-dioxan-5-yl)methyl, cyanomethyl, butanoyl, methoxyethyl, (3-hydroxypiperidino)carbonylmethyl, 1,2,4-oxadiazolylmethyl, (5-oxo)- 1,2,4- oxadiazolylmethyl, (5-methyl)- 1 ,2,4-oxadiazolylmethyl, (2-amino)- 1 ,3 ,4-oxadia
• R 3 is selected from hydrogen, hydroxyethyl, l,3-dihydroxyprop-2-yl, 2,3-dihydroxypropyl, 2,2-dimethyl-l,3-dioxan-5-ylmethyl, methylthioethyl, methanesulfinylethyl, methanesulfonylethyl, N- methanesulfonamidocarbonylethyl, amino(N-hydroxy)iminomethyl, methoxycarbonylmethyl, carboxymethyl, acetylaminoethyl, trifluoroacetylaminoethyl, hydroxymethylcarbonylmethyl, N-(pyrid-4-yl)carbamoylmethyl, N-(pyrid-2-yl)carbamoylmethyl, N-(3-methyl-pyrid-2- yl)carbamoylmethyl, N-(6-methyl- ⁇ yrid-2-
• R is selected from hydrogen, hydroxyethyl, hydroxypropyl, 2-butanol, 3-hydroxy-2-hydroxymethyl-propyl, 2,3-dihydroxypropyl, carbamoylmethyl, (dimethylcarbamoyl)methyl, (methylcarbamoyl)methyl,
• one of R 9 and R 10 is hydrogen and the other is selected from heterocyclyl and heterocyclyl(C ⁇ - alkyl).
• R 9 or R 10 as heterocyclyl and heterocyclyl(C ⁇ - alkyl) is selected from oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazoyl, thiadiazolyl, pyridyl, imidazolyl, furyl, thienyl, morpholine, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, piperazinyl.
• morpholinomethyl morpholinethyl, morpholinylmethyl, morpholinylethyl, piperidinomethyl, piperidinoethyl, piperidylmethyl, piperidylethyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl, 1 , 1 -dioxotetrahydrothiopyranyl, imidazolylmethyl, imidazolylethyl, oxazolylmethyl, oxazolylethyl, 1,3,4-oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl, pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl, pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and
• a preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0, 1 or 2; R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
• R is hydrogen; R 3 is selected from cyanoC ⁇ alkyl, and C ⁇ - 4 alkyl (optionally substituted by 1 or 2 R 8 groups);
• R 8 is independently selected from hydroxy, C 3 . cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci- 4 alkoxy, C ⁇ - 4 alkanoyl, C 1 - 4 alkylS(O)b- (wherein b is 0, 1 or 2), C 3 - 6 cycloalkylS(O)b- (wherein b is 0, 1 or 2), ary
• R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(Ci- alkyl), C ⁇ - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- alkyl substituted by C ⁇ alkoxy, and wherein R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl;
• R 11 is selected from hydrogen, C ⁇ - 4 alkyl and hydroxyC 1 - 4 alkyl; m is 1 or 2; and RR 44 iiss hhyyddrrooggeenn o or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• Another preferred class of compounds is of formula (1) wherein: is a single bond; A is phenylene; n is 0, 1 or 2; R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
• R 2 is hydrogen; R 3 is selected from C ⁇ - 4 alkyl (optionally substituted by 1 or 2 R 8 groups);
• R 8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, C ⁇ - 4 alkoxy, C !
• R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C 1 . 4 alkyl), C- ⁇ alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- alkyl substituted by Q ⁇ alkoxy, and wherein R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 6-membered ring selected from piperidine, 4-hydroxy piperidine, pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of 3,4- dihydroxypyrrolidine; m is 1 or 2; and R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• Another preferred class of compound is of the formula (1) wherein: is a single bond; A is phenylene; n is 0;
• R is hydrogen
• R 3 is selected from C ⁇ - 4 alkyl (optionally substituted by 1 or 2 R 8 groups);
• R 8 is independently selected from hydroxy, C 1 - 4 alkylS(O) b - (wherein b is 0, 1 or 2), -NHC(O)R 9 and -C(O)N(R 9 )(R 10 );
• R 9 and R 10 are independently selected from hydrogen, C ⁇ - 4 alkyl, heterocyclyl and heterocycly C ⁇ alkyl); m is 1 or 2; and
• R 4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a further preferred class of compound is of the formula (1) wherein; is a single bond;
• A is phenylene; n is 0, 1 or 2;
• R 1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy;
• R 2 is hydrogen
• R is selected from C ⁇ alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon); m is 1 or 2; R 4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0, 1 or 2;
• R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
• R 2 is hydrogen;
• R is selected from groups of the formulae B and B ' :
• R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a further preferred class of compound is of the formula (1) wherein; is a single bond;
• R 2 is hydrogen
• R 3 is hydroxypropyl, dihydroxypropyl or dihydroxybutyl; m is 1 or 2;
• R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0;
• R 2 is hydrogen
• R is hydroxypropyl, dihydroxypropyl or dihydroxybutyl; m is 1; R 4 is chloro; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0
• R 2 is hydrogen
• R 3 is heterocyclylcarbamoylmethyl; m is 1 or 2;
• R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• Another class of compounds is of the formula (1) wherein is a double bond; A is phenylene; n is 0, 1 or 2;
• R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
• R is carboxy
• R is selected from cyanoC ⁇ - 4 alkyl, and C 1 - 4 alkyl (optionally substituted by 1 or 2 R groups);
• R 8 is independently selected from hydroxy, C 3 - cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, C 1 - 4 alkoxy, C ⁇ - alkanoyl, Ci- alkylS(O) b - (wherein
• R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C 1 - alkyl), C ⁇ - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups) and Q- alkyl substituted by C 1 - 4 alkoxy and wherein R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl; R 11 is selected from hydrogen, Ci- 4 alkyl and hydroxyC 1 - alkyl; m is 1 or 2; and R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof
• a further class of compound is of formula (1) wherein: is a single bond
• A is heteroarylene; n is 0, 1 or 2;
• R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
• R 2 is hydrogen
• R is selected from cyanoC 1 - 4 alkyl, and C ⁇ alkyl (optionally substituted by 1 or 2 R groups)
• R 8 is independently selected from hydroxy, C 3 - 7 cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci- 4 alkoxy, C ⁇ - 4 alkanoyl, C 1 - 4 alkylS(O) b - (wherein b is 0, 1 or 2), C 3 -6cycloalkylS(O)b- (wherein b is 0, 1 or 2),
• R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C 1 . 4 alkyl), C 1 . 4 alkyl (optionally substituted by 1 or 2 hydroxy groups) and Q- 4 alkyl substituted by C ⁇ .
• R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl; R 11 is selected from hydrogen, Q- alkyl, hydroxyC ⁇ alkyl; m is 1 or 2; R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a further class of compound is of formula (1) wherein: is a single bond; A is heteroarylene; n is 0, 1 or 2;
• R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
• R 2 is hydrogen;
• R is selected from cyanoC ⁇ - alkyl, and C 1 - 4 alkyl (optionally substituted by 1 or 2 R groups)
• R 8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci- alkoxy, C ⁇ - 4 alkanoyl, Q- 4 alkylS(O) b - (wherein b is 0, 1 or 2), C 3 - 6 cycloalkylS(O) b - (wherein b is 0, 1 or 2), arylS(O) b -
• R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C 1 - 4 alkyl), Ci. 4 alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- 4 alkyl substituted by C ⁇ _ 4 alkoxy and wherein R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl; m is 1 or 2; and R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a further class of compound is of formula (1) wherein: is a single bond; A is heteroarylene; n is 0, 1 or 2;
• R 1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy;
• R 2 is hydrogen;
• R is selected from cyanoC 1 - 4 alkyl, and C ⁇ alkyl [optionally substituted by 1 or 2 R groups]; wherein R 8 is independently selected from -C(O)N(R 9 )(R 10 ), and -COOR 9 , R 9 and R 10 are independently selected from hydrogen, C ⁇ - 4 alkyl, heterocyclyl and heterocyclyl(C 1 - 4 alkyl); m is 1 or 2; and R 4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a further class of compound is of formula (1) wherein: is a single bond
• A is heteroarylene; n is 0, 1 or 2; R 1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy;
• R 2 is hydrogen
• R 3 is selected from C 1 - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups); m is 1 or 2; R 4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
• a preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 1 or 2; R 1 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl and
• R 1 is of the formula A' or A":
• R is selected from C 1 - alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyanoCi- 4 alkyl, and C- ⁇ alkyl [substituted by 1 or 2 R 8 groups (provided that when there are 2 R 8 groups they are not substituents on the same carbon)];
• ⁇ R 8 is independently selected from hydroxy, heterocyclyl, C ⁇ - 4 alkanoyl, Ci- 4 alkoxy, C ⁇ alkanesulfinyl, C ⁇ - 4 alkanesulfonyl, -COCOOR 9 , (R 9 )(R 10 )NCO-, -COCH 2 OR ⁇ , (R 9 )(R 10 )N-, -COOR 9 and 2,2-dimethyl-l,3-dioxolan-4-yl; [R 9 and R 10 are independently selected from hydrogen, hydroxy, C ⁇ - alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon) and C ⁇ - 4 alkyl substituted by C ⁇ - 4 alkoxy and wherein R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy
• R 11 is selected from hydrogen, C ⁇ - 4 alkyl, C ⁇ _ alkoxy and hydroxyC ⁇ - 4 alkyl] ⁇ ; m is 1 or 2;
• R 4 is hydrogen or halo.
• a further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 1 or 2; R 1 is independently selected from hydrogen, halo, nitro, hydroxy, C 1 - 4 alkyl and R 1 is of the formula A' or A":
• R 3 is selected from C 1 - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon); m is 1 or 2;
• R 4 is hydrogen or halo.
• preferred compounds of the invention are any one of:
• Another aspect of the present invention provides a process for preparing a compound of formula (1) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which process (wherein A, R 1 , R 2 , R 3 , R 4 , m, n and — are, unless otherwise specified, as defined in formula (1)) comprises of: a) reacting an acid of the formula (2):
• Acids of formula (2) and amines of formula (3) may be coupled together in the presence of a suitable coupling reagent.
• Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole, l-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride (EDCI) and dicyclohexyl-carbodiimide (DCCI), optionally in the presence of a catalyst such as 1- hydroxybenzotriazole, dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or such as 2,6-lutidine or 2,6-di-tert-butylpyridine.
• Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and di
• Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters.
• the reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above.
• the reaction may conveniently be performed at a temperature in the range of -40 to 40°C.
• R 3 of formula (1) contains an ester group
• the conversion of a compound of the formula (1) into another compound of the formula (1) may involve hydrolysis of the ester group for example, acid or base hydrolysis, for example using lithium hydroxide.
• the reaction of this type is well known in the art.
• R 3 of formula (1) contains -COOH group
• the conversion of a compound of the formula (1) into another compound of the formula (1) may involve reduction of this group using reducing agents such as lithium borohydride, sodium borohydride etc.
• the conversion may also involve the coupling of this -COOH group with ammonia or a substituted amine in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or 2,6-di- -.*iy ⁇ -pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine.
• a base for example triethylamine, di-isopropylethylamine, pyridine, or 2,6-di- -.*iy ⁇ -pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine.
• Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.
• Substituted amides wherein R 3 is CH 2 C(O)N(R 9 )(R 10 ) may be prepared from the corresponding acids by a coupling reaction using the appropriate amine in the presence of a coupling reagent, for example EDCI.
• the acid may first be converted to a mixed anhydride, by reaction with, for example, ethyl chloroformate, which is reacted with an appropriate amine to produce the substituted amide.
• CH 2 C(O)NHSO 2 R 9 may be prepared similarly, for instance by coupling the compounds wherein R 3 is CH 2 CO 2 H with the appropriate substituted sulphonamide in the presence of a coupling reagent, for example EDCI.
• a coupling reagent for example EDCI.
• Compounds of formula (1) wherein R 3 is 2-hydroxymethyl may be prepared by reduction of the mixed anhydrides described above with, for example, lithium borohydride.
• Compounds of formula (1) wherein R 3 is an oxadiazol-5-ylmethyl group may be prepared by reaction of the mixed anhydrides described above with an appropriately substituted hydroxyamidine, for example N'-hydroxyethanimidamide, in the presence of a base such as N- methylmorpholine.
• Compounds of formula (1) wherein R 3 is a tetrazol-5-ylmethyl group may be prepared by reaction of the corresponding compounds where R 3 is a cyanomethyl group with an azide, for example sodium azide, in the presence of an amine salt, for instance triethylamine hydrochloride.
• (methylsulphinyl)ethyl group may be prepared by reaction of the corresponding compounds where R 3 is 2-methylthioethyl with an oxidising agent, for example oxone.
• Compounds of formula (1) wherein R 3 is a dihydroxyalkyl group, for example 2,3- dihydroxypropyl or 2-(hydroxymethyl)-3-hydroxypropyl may be prepared by acid hydrolysis of the corresponding compounds of formula (1) wherein R 3 is a protected dihydroxyalkyl group for example (2,2-dimethyl-l,3-dioxan-5-yl)methyl, (2,2-dimethyl-l,3-dioxolan-4- yl)methyl or (2-oxo-l,3-dioxan-5-yl)methyl.
• the acids of formula (2) are commercially available or they are know compounds or they are prepared by processes known in the art.
• R 3 -L where L is a suitable leaving group (for example chloro, bromo or iodo) in the presence of a base such as sodium hydride in a suitable solvent.
• a suitable leaving group for example chloro, bromo or iodo
• Compounds of the formula (4) wherein A is phenylene and is a double bond may be prepared by the reductive cyclisation of a compound of formula (5), using for example tin (II) chloride in hydrochloric acid, followed by removal of the Boc protecting group, using for example trifluoroacetic acid.
• Compounds of formula (5) may be prepared by reaction of compounds of formula (6) by reaction with a compound of formula (7) in the presence of a base, for example tetramethylguanidine.
• Compounds of formula (6) are commercially available or described in the literature.
• Steps 1 and 2 may be carried out by the process described in Tetrahedron 1998, 54(23), 6311- 6318.
• Step 3 may be carried out by the method described in Synthesis 1992 (5) ,487.
• Step 4 Assymetric hydrogenation reactions of olefins as shown in Step 4 are well known (see for example, JACS 1993, 115, 10125-10138) and lead to homochiral final products.
• Step 5 may alternatively be carried out by hydrolysing the ester and activating the resulting acid with a carbodiimide such as EDCI or DCCI, or by preparing an acid chloride, or activated ester such as an N -hydroxysuccinimide ester.
• Suitable bases are organic base such as taethylamine or di-isopropylethylamine (DIPEA) or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
• Step 6 is a leaving group, for example CI, Br, I , OMesyl.
• Step 7 alternative solvents such as dichloromethane or other acids such as trifluoroacetic acid can be used.
• Steps 1, 2, 3 and 4 are described in JOC 1983, 48, 3401-3408.
• R 1 and R 4 may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention.
• Such reactions may convert one compound of the formula (1) into another compound of the formula (1).
• Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents.
• the reagents and reaction conditions for such procedures are well known in the chemical art.
• aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group.
• modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkanesulphinyl or alkanesulphonyl.
• a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
• the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
• a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
• a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
• the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
• the activity of the compounds is determined by measuring the inhibitory effect of the compounds in the direction of glycogen synthesis, the conversion of glucose- 1 -phosphate into glycogen with the release of inorganic phosphate, as described in EP 0 846 464 A2.
• the reactions were in 96well microplate format in a volume of lOO ⁇ l.
• the change in optical density due to inorganic phosphate formation was measured at 620nM in a Labsystems iEMS Reader MF by the general method of (Nordlie R.C and Arion W.J, Methods of Enzymology, 1966, 619-625).
• the reaction is in 50mM HEPES (N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid);4-(2-Hydroxyethyl)piperazine-l-ethanesulfonic acid), 2.5mM MgCl 2 , 2.25mM ethylene glycol-bis(b-aminoethyl ether) N,N,N',N'-tetraacetic acid, lOOmM KC1, 2mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution, with O.lmg type Dl glycogen, 0.15ug glycogen phosphorylase a (GP ⁇ ) from rabbit muscle and 0.5mM glucose-1-phosphate.
• HEPES N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid);4-(2-Hy
• GP is pre-incubated in the assay buffer solution with the type in glycogen at 2.5 mg ml "1 for 30 minutes. 40 ⁇ l of the enzyme solution is added to 25 ⁇ l assay buffer solution and the reaction started with the addition of 25 ⁇ l 2mM glucose- 1-phosphate.
• Compounds to be tested are prepared in lO ⁇ l 10% DMSO in assay buffer solution, with final concentration of 1% DMSO in the assay.
• the non-inhibited activity of GP ⁇ is measured in the presence of lO ⁇ l 10% DMSO in assay buffer solution and maximum inhibition measured in the presence of 30 ⁇ M CP320626 (Hoover et al (1998) J Med Chem 41, 2934-8; Martin et al (1998) P ⁇ AS 95, 1776-81).
• the reaction is stopped after 30min with the addition of 50 ⁇ l acidic ammonium molybdate solution, 12ug ml "1 in 3.48% H 2 SO 4 with 1% sodium lauryl sulphate and lOug ml "1 ascorbic acid. After 30 minutes at room temperature the absorbency at 620nm is measured.
• the assay is performed at a test concentration of inhibitor of lO ⁇ M or lOO ⁇ M. Compounds demonstrating significant inhibition at one or both of these concentrations may be further evaluated using a range of test concentrations of inhibitor to determine an IC 50 , a concentration predicted to inhibit the enzyme reaction by 50%. Activity is calculated as follows :-
• % inhibition (1 - (compound OD620 - fully inhibited OD620)/ (non-inhibited rate OD620 - fully inhibited OD620)) * 100.
• OD620 optical density at 620nM.
• Typical IC 5 0 values for compounds of the invention when tested in the above assay are in the range lOO ⁇ M to InM.
• the activity of the compounds is alternatively determined by measuring the inhibitory effect of the compounds on glycogen degradation, the production of glucose- 1 -phosphate from glycogen is monitored by the multienzyme coupled assay, as described in EP 0 846464 A2, general method of Pesce et al ( Pesce, M A, Bodourian, S H, Harris, R C, and Nicholson, J F (1977) Clinical Chemistry 23, 1171 - 1717).
• the reactions were in 384well microplate format in a volume of 50 ⁇ l.
• the change in fluorescence due to the conversion of the co-factor NAD to NADH is measured at 340nM excitation, 465nm emission in a Tecan Ultra Multifunctional Microplate Reader.
• the reaction is in 50mM HEPES, 3.5mM KH 2 PO 4 , 2.5mM MgCl 2 , 2.5mM ethylene glycol-bis -aminoethyl ether) N,N,N',N'-tetraacetic acid, lOOmM KCl, 8mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution.
• Human recombinant liver glycogen phosphorylase a (hrl GP ⁇ ) 20nM is pre-incubated in assay buffer solution with 6.25mM NAD, 1.25mg type Dl glycogen at 1.25 mg ml "1 the reagent buffer, for 30 minutes.
• the coupling enzymes phosphoglucomutase and glucose-6-phosphate dehydrogenase ( Sigma) are prepared in reagent buffer, final concentration 0.25Units per well. 20 ⁇ l of the hrl GPa solution is added to lO ⁇ l compound solution and the reaction started with the addition of 20ul coupling enzyme solution. Compounds to be tested are prepared in lO ⁇ l 5% DMSO in assay buffer solution, with final concentration of 1% DMSO in the assay. The non-inhibited activity of GP ⁇ is measured in the presence of lO ⁇ l 5% DMSO in assay buffer solution and maximum inhibition measured in the presence of 5mgs ml "1 N- ethylmaleimide. After 6 hours at 30°C Relative Fluoresence Units (RFUs) are measured at 340nM excitation, 465nm emission .
• REUs Relative Fluoresence Units
• the assay is performed at a test concentration of inhibitor of lO ⁇ M or lOO ⁇ M. Compounds demonstrating significant inhibition at one or both of these concentrations may be further evaluated using a range of test concentrations of inhibitor to determine an IC 5 o, a concentration predicted to inhibit the enzyme reaction by 50%. Activity is calculated as follows :-
• % inhibition (1 - (compound RFUs - fully inhibited RFUs)/ (non-inhibited rate RFUs - fully inhibited RFUs)) * 100.
• Typical IC 50 values for compounds of the invention when tested in the above assay are in the range lOO ⁇ M to InM.
• Example 14 was found to have an IC 5 o of 4.6 ⁇ m.
• Rat hepatocytes were isolated by the collagenase perfusion technique, general method of
• a pharmaceutical composition which comprises a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
• compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
• oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
• compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
• compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
• Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl r hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
• Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
• Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
• the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl rj-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
• the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
• the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
• Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening, flavouring and preservative agents.
• Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
• the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
• a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
• Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
• Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
• a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
• Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
• Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in
• the compound of formula (1) will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose.
• a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
• Preferably a daily dose in the range of 1-50 mg/kg is employed.
• the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
• glycogen phosphorylase activity described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets.
• simultaneous treatment may be in a single tablet or in separate tablets.
• n ellitus chemotherapy may include the following main categories of treatment:
• Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide) and prandial glucose regulators (for example repaglinide, nateglinide);
• sulphonylureas for example glibenclamide, glipizide
• prandial glucose regulators for example repaglinide, nateglinide
• Insulin sensitising agents including PPARg agonists (for example pioglitazone and rosiglitazone);
• Anti-obesity agents for example sibutramine and orlistat
• Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (statins, eg pravastatin); PPAR ⁇ agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); bile acid absorption inhibitors (IBATi) and nicotinic acid and analogues (niacin and slow release formulations);
• Antihypertensive agents such as, ⁇ blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), antagonists and diuretic agents (eg. furosemide, benzthiazide);
• ⁇ blockers eg atenolol, inderal
• ACE inhibitors eg lisinopril
• Calcium antagonists eg. nifedipine
• Angiotensin receptor antagonists eg candesartan
• antagonists and diuretic agents eg. furosemide, benzthiazide
• Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor VHa inhibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; and 11) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).
• a compound of the formula (1) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use in a method of treatment of a warm-blooded animal such as man by therapy.
• a compound of the formula (1) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity in a warm-blooded animal such as man.
• a method of producing a glycogen phosphorylase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (1).
• a method of treating type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity which comprises administering to said animal an effective amount of a compound of formula ( 1 ) .
• a method of treating type 2 diabetes in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (1).
• a dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
• a unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
• the compounds of formula (1) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
• temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C and under an atmosphere of an inert gas such as argon;
• KP-SILTM silica 60 ⁇ , particle size 32-63mM, supplied by Biotage, a division of Dyax Corp.
• NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO- ⁇ 6 ) as solvent unless otherwise indicated, other solvents (where indicated in the text) include deuterated chloroform
• Example 2 N-ri-CCarboxymethvD- -oxo-l ⁇ -tetrahvdroquinolin-S-yll-S- chloroindole-2-carboxamide;
• Example 11 5-chloro-N-( 1 - ⁇ 2- [(5-methyl- 1 ,3 ,4-thiadiazol-2-yl)amino] -2-oxoethyl ⁇ -2-oxo- l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 12 5-chloro-N-(l- ⁇ 2-[(5-ethyl-l,3,4-thiadiazol-2-yl)aminol-2-oxoethyll-2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 13 5-chloro-N-(l- ⁇ 2-r(4-cvano-lH-pyrazol-3-yl)amino]-2-oxoethyl
• Example 14 5-chloro-N-(l- ⁇ 2-[(4-methyl-l,3-thiazol-2-yl)aminol-2-oxoethyl ⁇ -2-oxo- 1,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
• Example 16 5-chloro-N-( 1- ⁇ 2-[(3-hvdroxypyridin-2-yl)aminol -2-oxoethyl ) -2-oxo- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 17 5-chloro-N-(2-oxo- 1 - ⁇ 2-oxo-2-[(pyridin-2-ylmethyl)amino1ethyl 1-1.2.3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 19 5 -chloro-N-( 1 - ⁇ 2- r 1 -methyl- lH-pyrazol-5-yl)amino] -2-oxoethyl I -2-oxo- 1 ,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
• Example 20 5-chloro-N-(l- ⁇ 2-[(l,3-dimethyl-lH-pyrazol-5-yl aminol-2-oxoethyll-2-oxo- l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 21 5-chloro-N-(2-oxo-l- ⁇ 2-oxo-2-[(pyrazin-2-ylmethyl)aminolethyl
• Example 22 5-chloro-N-(l- ⁇ 2-[f6-fluoropyridin-3-yl)aminol-2-oxoethyl ⁇ -2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 25 5-chloro-N-( 1 - ⁇ 2- [( 1 -ethyl- lH-pyrazol-5-yl)amino] -2-oxoethyl ⁇ -2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 26 5-chloro-N-(2-oxo- 1- ⁇ 2-oxo-2- [(5-oxo-4,5-dihydro- lH-pyrazol-3- vDaminol ethyl 1-1,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
• Example 27 5-chloro-N-( 1 - ⁇ 2- ⁇ ( 4-hvdroxypyrimidin-2-yl)amino1 -2-oxoethyl ⁇ -2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 28 5-chloro-N-(l- ⁇ 2-r(3-methylpyridin-2-yl)aminol-2-oxoethv ⁇ -2-oxo-l,2,3.4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 29 5-chloro-N-(l- ⁇ 2-[(6-chloropyridazin-3-yl)amino]-2-oxoethyl]-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 30 5-chloro-N-( 1- ⁇ 2- ( lH-imidazol-2-ylmethyl)amino1 -2-oxoethyl I -2-oxo-
• Example 32 5-chloro-N- ( 2-oxo- 1 - [2-oxo-2-(2H-tetrazol-5-ylamino)ethyl1- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl
• Example 34 5-chloro-N-(l- ⁇ 2-[(5-fluoropyridin-2-yl)amino1-2-oxoethyl ⁇ -2-oxo-l,2,3,4- tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
• Example 35 N-( 1 - ⁇ 2-[(6-bromopyridin-3-yl)amino1-2-oxoethyl I -2-oxo- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl)-5-chloro-lH-indole-2-carboxamide
• Triethylamine (0.168 mL, 1.21 mmol) then ethyl chloroformate (0.115 mL, 1.21 mmol) were added to N-[l-(carboxymethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5- chloroindole-2-carboxamide (Example 2, 437 mg, 1.10 mmol) in anhydrous THF (10 mL) at 0 °C followed by stirring for 1 h.
• LiBHt 2.0 M in THF, 0.69 mL, 1.37 mmol
• Example 38 5-Chloro-N-(l-r3-hvdroxy-2-(hvdroxymethvI)propyl1-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indoIe-2-carboxamide
• Example 37 The procedure of Example 37 was followed using 3-amino-l-[(2,2-dimethyl-l,3- dioxolan-4-yl)methyl]-3,4-dihydroquinolin-2(lH)-one (Method 5) as amine and 5-Chloro- l ⁇ -indole-2-carboxylic acid as the acid component, to give the title compound as a white solid which was used without purification and subjected to acid catalysed hydrolysis according to the method used for Example 38 gave the title compound (90%) as a white solid.
• Dess-Martin Periodinane 120 mg, 0.28 mmol was added to a stirring solution of N- [l-(3- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-hydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl] -5 -chloro- lH-indole-2-carboxamide (Method 6, 74 mg, 0.14 mmol) in DCM and the reaction was stirred for 2 hours. The reaction was quenched by addition of sat. aqueous
• Example 42 5-Chloro-N-(l- ⁇ 2-[(methylsulfonyl)amino1ethyl ⁇ -2-oxo-1.2.3.4- tetrahvdroquinolin-3-yl)-lH-indoIe-2-carboxamide
• Triethylamine (80 ⁇ L, 0.6 mmol) was added to a stirred suspension of N-[l-(2- aminoethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5-chloro-lH-indole-2-carboxamide_ trifluoroacetate (Method 9, 150 mg, 0.3 mmol) and methanesulfonyl chloride (25 ⁇ L, 0.33 mmol) in anhydrous DCM (5 mL) at 0 °C. The reaction was stirred at 0°C for 30 rnins, then warmed and stirred at ambient temperature for 30 rnins.
• reaction was stirred for 90 rnins at ambient temperature, diluted with EtOAc (5 mL), washed with 1 ⁇ ⁇ aO ⁇ (3 mL), 1 N HCl (3 mL), saturated aqueous NaHCO 3 solution (5 mL) and dried (MgSO ).
• Triethylamine (184 ⁇ L, 1.32 mmol), HOBt (89 mg, 0.66 mmol), 3-amino-6-fluoro-3,4- dihydro-2(lH)-quinolinone monohydrochloride (CAS Reg. No: 82420-54-0) (143 mg, 0.66 mmol), and ED AC (127 mg, 0.66 mmol) were added to a solution of 5-chloroindole-2- carboxylic acid (129 mg, 0.66 mmol) in anhydrous DMF (3.5 mL). The reaction was stirred at ambient temperature for approximately 16 h, and then poured into water (50 mL). This was stirred vigorously for about 10 mins. and filtered. The collected precipitate was washed with water and dried in vacuum at 40°C, to give the title compound (200 mg, 85%) as an amorphous solid.
• Example 48 5-ChIoro-N-[6-(methyIoxy)-2-oxo-1.2.3,4-tetrahydroquinoIin-3-yn-lH- indole-2-carboxamide
• reaction was quenched by addition of IM aqueous ⁇ C1 (5 mL) and the volatiles were removed by evaporation. The residue was dissolved in DCM (250 mL) and washed with sat. aqueous Na ⁇ CO 3 (100 mL) and the organic layer was dried (MgSO 4 ), filtered and evaporated to yield the title compound (5.89 g, 100%) as yellow paste which was used in the next reaction 0 without further purification.
• N-Hydroxysuccinimide (496 mg, 4.31 mmol) and EDCI (1.04g, 5.38 mmol) were added to a suspension of N-[l-(carboxymethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5- chloroindole-2-carboxamide (Example 2, 1.71 g, 4.31 mmol)) in DCM (50 mL) and stirred for 18 hours. The suspension was evaporated and the residue partitioned between EtOAc:THF (4:1)(200 mL) and H 2 O. The organic was dried ( ⁇ a 2 SO 4 ), filtered and evaporated.
• DIPEA (0.27 mL, 1.55 mmol) and then EDCI (370 mg, 1.94 mmol) were added to a solution of 3-amino-l- ⁇ [(4R)-2,*2-dimethyl-l,3-dioxolan-4-yl]methyl ⁇ -3,4-dihydroquinolin-2(lH)-one (Method 8, 428 mg, 1.55 mmol) in DCM (10 mL).
• the title compound was prepared in an analogous method to Method 1 using (3- bromopropoxy)(tert-butyl)dimethylsilane as elecrophile.

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• Obesity (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Emergency Medicine (AREA)
• Endocrinology (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Child & Adolescent Psychology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Indole Compounds (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (2)

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Cited By (17)

Families Citing this family (2)

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• 2002
  • 2002-03-06 GB GBGB0205162.1A patent/GB0205162D0/en not_active Ceased
• 2003
  • 2003-03-04 JP JP2003572981A patent/JP2005525364A/ja not_active Withdrawn
  • 2003-03-04 US US10/506,748 patent/US7169927B2/en not_active Expired - Fee Related
  • 2003-03-04 WO PCT/GB2003/000893 patent/WO2003074513A2/en not_active Ceased
  • 2003-03-04 EP EP03712313A patent/EP1485371A2/en not_active Withdrawn
  • 2003-03-04 AU AU2003216991A patent/AU2003216991A1/en not_active Abandoned
  • 2003-03-05 TW TW092104667A patent/TW200403233A/zh unknown
  • 2003-03-06 AR ARP030100767A patent/AR038887A1/es unknown

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